US5364644A - Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders - Google Patents

Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders Download PDF

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US5364644A
US5364644A US08/012,145 US1214593A US5364644A US 5364644 A US5364644 A US 5364644A US 1214593 A US1214593 A US 1214593A US 5364644 A US5364644 A US 5364644A
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glucarate
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Zbigniew Walaszek
Thomas J. Slaga
Margaret Hanausek
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University of Texas System
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/03Organic compounds
    • A23L29/035Organic compounds containing oxygen as heteroatom
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12Fatty acids or derivatives thereof
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15Vitamins
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16Inorganic salts, minerals or trace elements
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23LFOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17Amino acids, peptides or proteins
    • A23L33/175Amino acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/194Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/42Phosphorus; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/06Antihyperlipidemics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23VINDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Hypercholesterolemia and cellular hyperproliferative disorders are causative factors in several different pathologies, many of which cause death.
  • hypercholesterolemia also including hyperlipidemia for purposes of the present invention, is a contributing factor in the development of heart disease and stroke.
  • Heart disease is the single biggest cause of death in the United States.
  • Cellular hyperproliferative disorders include such diseases as psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma; chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, proliferative diseases of retinal cells, and some cancers. Although several of the cellular proliferative disorders only cause discomfort and patient suffering, several, such as cancer, may be fatal. In the United States alone, tens of thousands of people die from cancer each year, and additional tens of thousands suffer from the numerous other cellular hyperproliferative disorders.
  • Arteriosclerosis is a major factor in the development of heart disease and stroke.
  • various dietary components such as, lipids, proteins, carbohydrates, dietary fibers, and trace metals, have been investigated. It is commonly assumed that plethoric diets high in fats and cholesterol are a major cause in the development of hypercholesterolemia.
  • plethoric diets are known to be associated with increased levels of low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL) (1,2).
  • LDL low density lipoproteins
  • VLDL very low density lipoproteins
  • HDL high density lipoproteins
  • Serum cholesterol levels that are generally accepted as within normal ranges in the United States are higher than those found among comparable individuals in populations with a low incidence of arteriosclerosis.
  • the optimal serum cholesterol for a middle-aged American man is probably about 200 mg/100 ml, or less.
  • hypercholesterolemia is generally defined as any value above the 95th percentile for the population, which in Americans ranges from about 230 mg/100 ml in individuals less than 20 years old, to about 300 mg/100 ml in individuals greater than 60 years old. These limits are, however, probably excessive because of the known risk of cholesterol values at these levels.
  • practicing physicians frequently use a convenient rule of thumb which holds that any level of serum cholesterol greater than about 200 mg/100 ml plus the person's age should be considered abnormal. Even these limits may be too high.
  • diet modification e.g., the strict avoidance of the sources of cholesterol and saturated fats.
  • the patient is instructed to avoid meat, especially organ meats and obviously fat, egg, whole milk, cream, butter, lard, and saturated cooking fats.
  • These foods are replaced in the patient's diet with foods low in saturated fat and cholesterol, e.g., fish, vegetables, poultry, polyunsaturated oils, and margarine.
  • saturated fat and cholesterol e.g., fish, vegetables, poultry, polyunsaturated oils, and margarine.
  • this therapy requires a dramatic lifestyle change and the substituted foods are generally less flavorful, patient compliance is very poor.
  • cholestyramine a bile acid sequestrant
  • a dosage of about 16 to about 32 grams in 2 to 4 divided daily doses will, for example, lower LDL levels by 25 to 50%, probably by increasing LDL removal.
  • cholestyramine is associated with side effects, such as constipation and poor taste that limit general patient acceptance.
  • cholestyramine and another hypocholesterolemic drug, candicidin apparently increased azoxymethanol-induced bowel tumorigenesis in the rat (3,4).
  • niacin is useful in hypercholesterolemia, but the high dosage required, three to nine grams per day in divided dosage with meals, coupled with the side effects of gastric irritability, hyperuricemia, hyperglycemia, flushing and pruritus, prevents its general use. Niacin is most effective when combined with cholestyramine.
  • Thyroid analogs e.g., D-thyroxine
  • Thyroid analogs effectively lower LDL levels, but are contraindicated in patients with suspected or proven heart disease. Further, since these agents mimic thyroid hormone, they produce a plethora of untoward effects in the body. Accordingly, these agents have no little or no place in the therapy of the typical hypercholesterolemia patient. Other agents which are presently utilized are generally less effective than strict dietary management.
  • Heart disease kills tens of thousands of Americans every year.
  • the major cause of heart disease is the accumulation of plaque in the coronary arteries. This accumulation is presumably cause by excessively high levels of serum cholesterol.
  • hypocholesterolemic agent commercially available that has found wide patient acceptance.
  • hypocholesterolemic agent which effectively lowers serum cholesterol in a human without the attending side effects typically associated with previous hypocholesterolemic agents. Further, it would be advantageous to provide a hypocholesterolemic agent which is effective when administered to a patient in need thereof in a relatively small dose. Another and important advantage is realized by providing a hypocholesterolemic agent which is administered multiple times or once daily, particularly if a slow release formulation is used. It would also be advantageous to provide a hypocholesterolemic agent which is incorporated into a vehicle, such as a multivitamin and mineral tablet, and administered daily to the general population to prophylactically protect the population against hypercholesterolemia. A still further advantage would be realized in providing a hypocholesterolemic agent which is safely, and inexpensively added to foodstuffs intended for consumption by the general population, and thereby provide prophylactic protection against hypercholesterolemia.
  • Cellular hyperproliferative disorders are generally characterized by the hyperproliferation and incomplete differentiation of cells. For example, in psoriasis vulgaris there is a hyperproliferation of incompletely differentiated cells of the epidermis. Presently, it is not fully understood what causes certain cells to reproduce rapidly when the host has no apparent need for them. Since growing evidence suggests that cellular hyperproliferation is involved with chemically induced carcinogenesis, the inhibition of cellular proliferation may also be an effective tool for prevention of certain cancers.
  • the inhibition of cellular proliferation may be an effective tool for preventing psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several other diseases associated with the hyperproliferation of cells such as chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, or hairy cell leukemia, or proliferative diseases of retinal cells, for example.
  • diseases associated with the hyperproliferation of cells such as chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, or hairy cell leukemia, or proliferative diseases of retinal cells, for example.
  • an antiproliferation agent which effectively inhibits cellular hyperproliferation in a human
  • an antiproliferative agent which is effective when administered to a patient in need thereof in a relatively small dose. Another and important advantage is realized by providing an antiproliferative agent which may be administered once daily. It would also be advantageous to provide an antiproliferative agent which is incorporated into a vehicle, such as a multivitamin and mineral tablet, and administered daily to the general population to prophylactically protect the population against cellular hyperproliferation. A still further advantage would be realized in providing an antiproliferative agent which is safely, and inexpensively added to foodstuffs intended for consumption by the general population, and thereby provide prophylactic protection against the disease typically associated the with hyperproliferation of cells.
  • One aspect of the invention is directed to a method for the prevention and treatment of hypercholesterolemia.
  • a further aspect of the present invention is directed to a method for the prevention and treatment of cellular hyperproliferation.
  • an animal is administered a pharmaceutical formulation including a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
  • the animal is preferably a human.
  • the pharmaceutical formulation may be a tablet, capsule, suspension, or solution.
  • the pharmaceutical formulation may be administered by mouth or by injection.
  • the pharmaceutically acceptable salt is preferably selected from the groups consisting of calcium glucarate, sodium glucarate, potassium hydrogen glucarate, and magnesium glucarate.
  • a human is administered daily a sustained release pharmaceutical formulation including from about 200 mg to about 8,000 mg of glucaric acid or a pharmaceutical acceptable salt thereof.
  • the pharmaceutical formulation also includes a multiplicity of vitamins, minerals and micronutrients. The preparation is intended as prophylactic protection against the onset of hypercholesterolemia and cellular hyperproliferation.
  • a method for the prevention of hypercholesterolemia and/or cellular hyperproliferation in a population of humans and animals.
  • the method provides for adding to a selected foodstuff a predetermined amount of glucaric acid or a pharmaceutical acceptable salt thereof, and thereafter, providing a sufficient quantity of the foodstuff to the population of humans and animals such that the humans and animals ingest a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
  • the present invention provides a formula and method for the treatment of hypercholesterolemia and cellular hyperproliferation. More specifically, the present invention provides a method for administering a formula including glucaric acid or a pharmaceutically acceptable salt thereof for the prevention and treatment of hypercholesterolemia and cellular hyperproliferation in humans and animals. It has been determined that glucaric acid, and the pharmaceutically acceptable salts thereof, significantly lower the total level of serum cholesterol and LDL in animals when administered in therapeutic amounts while simultaneously inhibiting cellular hyperproliferation. It is intended that glucaric acid or a pharmaceutically acceptable salt thereof is employed alone or in combination with other medicinal agents for the prevention and treatment of hypercholesterolemia and/or cellular hyperproliferation.
  • D-Glucaric acid is a six-carbon, straight-chain dicarboxylic acid and is sometimes referred to as D-saccharic acid. Chemically, a schematic formula for D-glucaric acid is COOH--(CHOH) 4 --COOH.
  • the salts of D-glucaric acid (glucaric acid) are referred to as D-glucarates (glucarates), e.q., calcium glucarate, sodium glucarate, magnesium glucarate, and potassium hydrogen glucarate.
  • Glucaric acid and the salts thereof are normal metabolic products in mammals.
  • glucuronic acid was found to be enzymatically oxidized to glucaric acid.
  • Glucaric acid is the sole end product of the glucuronic acid pathway in guinea pigs and primates (7).
  • Significant interindividual differences have been reported (8) in normal healthy populations. It was observed (9) that the urinary excretion of glucaric acid in cancer patients and tumor-bearing rats was significantly lower than in healthy controls.
  • uninvolved liver tissue was found to have a lowered glucaric acid level (7). Further, studies have shown that cancerous tissues lack the glucaric acid-synthesizing system (7).
  • glucaric acid/glucarate The physiological function of glucaric acid/glucarate remains unclear, although it appears to be an important carbohydrate for cell viability and homeostasis. It is not known if glucaric acid is an essential nutrient for normal subjects. Some plants have been analyzed as identifiable sources rich in glucaric acid (10, 11). Recently glucaric acid/glucarate have been found in cruciferous vegetables (12). Glucaric acid/glucarate content is high in young seedlings and sprouts but low in respective seeds (13). Glucaric acid/glucarates are generally non-toxic, and no adverse effects have been observed from prolonged feeding of potassium hydrogen glucarate to rats (14, 15) or calcium glucarate to rats (16) and mice (17).
  • a medicament including therapeutic amounts of glucaric acid or a pharmaceutically acceptable salt thereof useful in the treatment and prevention of hypercholesterolemia cellular and hyperproliferation.
  • glucaric acid or a pharmaceutically acceptable salt thereof useful in the treatment and prevention of hypercholesterolemia cellular and hyperproliferation.
  • the present inventors have determined that, by administering therapeutic amounts of glucaric acid/glucarate, total serum cholesterol could be significantly reduced. Studies with this compound demonstrated that HDL, LDL, and VLDL were reduced and, most significantly, serum LDL was reduced. Further, studies have shown that glucarates are generally non-toxic and cause little or no side effects in the individual being treated.
  • glucaric acid inhibits cellular hyperproliferation in animals. Since cellular hyperproliferation is related not only to the development of certain cancers but also other diseases, e.g., psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several proliferative disorders, it is believed that the use of glucarates for this purpose would be a significant departure from prior method of preventing or treating diseases associated with cellular hyperproliferation.
  • diseases e.g., psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several proliferative disorders
  • a method wherein an individual in need thereof is administered a pharmaceutical formulation including a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
  • the inventive method is intended to reduce cholesterol in those individuals suffering from hypercholesterolemia and to inhibit cellular hyperproliferation in those individuals in need thereof. Further the formulation and method is intended to prevent the onset of hypercholesterolemia and/or cellular hyperproliferation in those individuals at risk of developing it.
  • the present inventors have demonstrated that glucarates significantly lower total serum cholesterol in rats, and it is believed that this therapeutic effect will also be observed in humans. Moveover, the present inventors have also demonstrated that glucarates inhibit cellular proliferation. It is intended that this discovery be applied beneficially to treat those individuals suffering from cellular hyperproliferation disorders.
  • Glucaric acid or glucarates may be compounded in numerous acceptable pharmaceutical formulations.
  • Preferable pharmaceutical formulations include tablets, capsules, insuflations, syrups, suspensions, solutions, suppositories, injections, and any sustained release preparation thereof. More preferable, the compound is incorporated into a sustained release tablet or capsule which will provide a hypocholesterolemic and antiproliferative therapeutic effect for the longest possible duration. Thus, the individual receives the maximum benefit from the compound, and patient compliance is increased because the dosage form is administered daily.
  • Injections which are useful in the practice of the present invention include intravascular (e.g., intravenous or intraarterial) subcutaneous, intramuscular, intralymphatic, intraperitoneal, and intrapleural. The most preferable route of the administration for an injection is, however, intravenous.
  • the pharmaceutical formulation administered to the individual in need thereof preferably includes a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
  • the individual is administered daily from about 10 mg to about 16,000 mg of glucaric acid or a pharmaceutically acceptable salt thereof per day compounded as a single or divided dose. More preferably the individual is administered from about 200 mg to about 8,000 mg per day.
  • the preferred pharmaceutically acceptable salt of glucaric acid includes any salt of glucaric acid which is both non-toxic and does not substantially diminish the therapeutic effect of the compound.
  • preferred pharmaceutically acceptable salts of glucaric acid include calcium glucarate, sodium glucarate, magnesium glucarate, and potassium hydrogen glucarate. More preferably, however, the pharmaceutical formulation includes potassium hydrogen glucarate and/or calcium glucarate.
  • glucaric acid and/or glucarate is incorporated as a hypocholesterolemic or antiproliferative agent into nutritional compositions containing vitamins, minerals and/or other micronutrients, e.g., a multivitamin and mineral preparation.
  • the glucarate moiety acts as a carrier for minerals such as calcium and potassium.
  • glucarates are included in therapeutic, non-toxic, amounts in a multivitamin supplement as a preventive measure to protect the general population against the onset of hypercholesterolemia and/or cellular hyperproliferation.
  • Such formulas may be prepared according to manufacturing techniques well know in the pharmaceutical art, and in a variety of dosage forms, such as, tablets, capsules, and liquids or sustained release formulations thereof.
  • glucaric acid and/or glucarates are incorporated in therapeutic amounts into foodstuffs and are consumed by the general population.
  • many foodstuffs are enriched by the addition of vitamins and mineral supplements, for example, breads, cereals, milk and fruit juices.
  • Glucarates may be added to these products in the same conventional manner in which vitamins or minerals are added to enrich foods.
  • calcium glucarate or potassium hydrogen glucarate may be added to a food product, thereby advantageously providing both a mineral supplement, e.g., calcium and potassium, and prophylactic protection against the onset of hyperproliferative diseases and hypercholesterolemia.
  • the further enrichment of these products with glucaric acid and/or a glucarate will advantageously provide the consuming public with an inexpensive, safe, and convenient alternative for preventing the onset of hyperproliferative diseases and hypercholesterolemia.
  • glucarates are safe, effective hypocholesterolemic and antiproliferation agents.
  • glucarate is preferably utilized or administered in combination with a multivitamin and mineral formulation.
  • a formulation is administered as a single sustained release dose.
  • Calcium D-glucarate was incorporated to the AIN-76A diet (18, 19) at the concentration of 17.5 or 35 mmol/kg diet with no changes in the level of any essential micronutrient. Specifically there was no change in the level of calcium and phosphorus.
  • the AIN-76A or glucarate-containing AIN-76A diets were fed ad libitum to female Sprague-Dawley rats beginning at 40 days of age. Food intake and body weight were monitored periodically. There was no statistically significant difference in food intake or weight gain. DNA labeling indices were measured in 55-day-old rats. Four animals from each dietary group were injected at 9:00 a.m.
  • the blood serum was obtained from rats and analyzed for their total cholesterol, triglycerides and lipoprotein cholesterol (21).
  • the test methodologies all run on a Roche Cobas Mira according to the procedure recommended by manufacturer, were as follows. Total cholesterol was assayed using a sequential enzymatic reaction forming a quinoneimmine dye in one step. Triglycerides in serum were hydrolyzed by lipase to free fatty acids and glycerol to form red chromogen.
  • HDL was separated by isoelectric-polyanionic precipitation of LDL, using phosphotungstate as precipitation reagent.
  • HDL cholesterol (HDL-C) was then assayed as described above for total cholesterol.
  • dietary glucarate significantly and in a dose dependent fashion reduced serum levels of total cholesterol.
  • the LDL cholesterol reduction by glucarate (35 mmol/kg diet) was also significant. There were no significant differences in triglyceride, HDL-C or VLDL-C levels.
  • Rats Six week-old male Sprague-Dawley rats received a single subcutaneous injection of azoxymethane (15mg/kg body weight) (22). Rats were fed normal chow diets containing 140 mmol/kg of either calcium glucarate or calcium gluconate (negative calcium control) beginning 1 week before carcinogen administration. Animals were sacrificed 8 months post-carcinogen treatment and evaluated for the presence of tumors.
  • the contents of the AIN-76 Mineral Mixture and the AIN-76A Vitamin Mixture are shown in Tables 4 and 5, respectively. These mineral and vitamin mixtures, known from the prior art, were used to prepare the AIN-76A diet used as control diet in Example 1.
  • a normal fat diet (pelleted corn starch AIN-76A diet) and a high fat diet containing 5% and 20% fat, respectively, were prepared as described in the prior art (Dyets, Inc. 1981/1988 catalog: Experimental Diets & Ingredients for Laboratory Animals).
  • Two high fat diets were prepared by incorporating potassium hydrogen D-glucarate at the concentration of 17 or 34 mmol/kg diet using the mineral formulas 3 and 4 as described in Example 4 (see Table 6).
  • Female virgin Sprague-Dawley rats were fed these experimental diets or control diets for 4 weeks beginning at 44 days of age. The rats were sacrificed and the blood was assayed for total cholesterol, total triglycerides, HDL-C, LDL-C and VLDL-C as described in Example 1. The results are shown in Table 8.
  • the hypercholesterolemic high fat diet increased the serum levels of total cholesterol and LDL cholesterol 1.2-fold and 2.3-fold, respectively. However, the increased total cholesterol and LDL cholesterol levels were reduced 12% (p ⁇ 0.05) and 35% (0.02) respectively by using the glucarate mineral Formula 3 of Example 4 (34 mmol glucarate per kg high fat diet).
  • Table 11 shows the vitamin and mineral content of a pharmaceutical formula with glucarate provided in the form of potassium hydrogen D-glucarate.
  • Table 14 The contents of a chemically defined diet with glucarate is shown in Table 14. This is an example of a nutritionally complete, elemental diet for enteral nutrition. Table 15 describes acceptable ranges of these components.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention provides a formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferation. More specifically, the present invention provides a method for administering a formula including glucaric acid or a pharmaceutically acceptable salt thereof for the prevention and treatment of hypercholesterolemia and cellular hyperproliferation in humans and animals. It has been determined that glucaric acid and pharmaceutically acceptable salts thereof significantly lower the total and LDL level of serum cholesterol and inhibit cellular hyperproliferation when administered in therapeutic amounts. It is intended that glucaric acid or a pharmaceutically acceptable salt thereof is employed alone or in combination with other medicinal agents for the prevention and treatment of hypercholesterolemia and cellular hyperproliferation.

Description

The Government has certain rights to this invention pursuant to National Institutes of Health Grant CA 47342.
This application is a continuation of U.S. patent application Ser. No. 07/525,384, filed May 16, 1990, NOW ABANDONED.
BACKGROUND OF THE INVENTION
Hypercholesterolemia and cellular hyperproliferative disorders are causative factors in several different pathologies, many of which cause death. For example, hypercholesterolemia, also including hyperlipidemia for purposes of the present invention, is a contributing factor in the development of heart disease and stroke. Heart disease is the single biggest cause of death in the United States. Cellular hyperproliferative disorders include such diseases as psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma; chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, proliferative diseases of retinal cells, and some cancers. Although several of the cellular proliferative disorders only cause discomfort and patient suffering, several, such as cancer, may be fatal. In the United States alone, tens of thousands of people die from cancer each year, and additional tens of thousands suffer from the numerous other cellular hyperproliferative disorders.
High levels of blood cholesterol and blood lipids are conditions involved in the onset of arteriosclerosis. Arteriosclerosis is a major factor in the development of heart disease and stroke. Among the numerous studies into the origin of hyperlipidemia, and familiar hypercholesterolemia, various dietary components, such as, lipids, proteins, carbohydrates, dietary fibers, and trace metals, have been investigated. It is commonly assumed that plethoric diets high in fats and cholesterol are a major cause in the development of hypercholesterolemia. Moreover, plethoric diets are known to be associated with increased levels of low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL) (1,2).
Studies have shown that the incidence of coronary heart disease rises in linear fashion with the level of serum cholesterol. In the United States coronary heart disease kills many thousands of people annually. Because high serum cholesterol levels are directly related to coronary heart disease, reducing serum cholesterol levels is a major health concern in the United States.
Serum cholesterol levels that are generally accepted as within normal ranges in the United States are higher than those found among comparable individuals in populations with a low incidence of arteriosclerosis. The optimal serum cholesterol for a middle-aged American man is probably about 200 mg/100 ml, or less. For practical purposes, hypercholesterolemia is generally defined as any value above the 95th percentile for the population, which in Americans ranges from about 230 mg/100 ml in individuals less than 20 years old, to about 300 mg/100 ml in individuals greater than 60 years old. These limits are, however, probably excessive because of the known risk of cholesterol values at these levels. As an alternative method, practicing physicians frequently use a convenient rule of thumb which holds that any level of serum cholesterol greater than about 200 mg/100 ml plus the person's age should be considered abnormal. Even these limits may be too high.
Once a patient has been diagnosed as suffering from hypercholesterolemia the first, and most common, method of therapy is diet modification, e.g., the strict avoidance of the sources of cholesterol and saturated fats. The patient is instructed to avoid meat, especially organ meats and obviously fat, egg, whole milk, cream, butter, lard, and saturated cooking fats. These foods are replaced in the patient's diet with foods low in saturated fat and cholesterol, e.g., fish, vegetables, poultry, polyunsaturated oils, and margarine. However, because this therapy requires a dramatic lifestyle change and the substituted foods are generally less flavorful, patient compliance is very poor.
Once it is determined that dietary restrictions have not accomplished the desired end, pharmaceutical therapy is instituted. Hypocholesterolemic agents enjoy wide use and acceptance in the medical community as an alternative to dietary restrictions. Cholestyramine, a bile acid sequestrant, is a hypocholesterolemic agent which is effective in lowering serum cholesterol, especially when coupled with diet restrictions. A dosage of about 16 to about 32 grams in 2 to 4 divided daily doses will, for example, lower LDL levels by 25 to 50%, probably by increasing LDL removal. However, cholestyramine is associated with side effects, such as constipation and poor taste that limit general patient acceptance. Further, cholestyramine and another hypocholesterolemic drug, candicidin, apparently increased azoxymethanol-induced bowel tumorigenesis in the rat (3,4).
A further hypocholesterolemic agent, niacin is useful in hypercholesterolemia, but the high dosage required, three to nine grams per day in divided dosage with meals, coupled with the side effects of gastric irritability, hyperuricemia, hyperglycemia, flushing and pruritus, prevents its general use. Niacin is most effective when combined with cholestyramine.
Thyroid analogs, e.g., D-thyroxine, effectively lower LDL levels, but are contraindicated in patients with suspected or proven heart disease. Further, since these agents mimic thyroid hormone, they produce a plethora of untoward effects in the body. Accordingly, these agents have no little or no place in the therapy of the typical hypercholesterolemia patient. Other agents which are presently utilized are generally less effective than strict dietary management.
Heart disease kills tens of thousands of Americans every year. The major cause of heart disease is the accumulation of plaque in the coronary arteries. This accumulation is presumably cause by excessively high levels of serum cholesterol. However, there is still no effective hypocholesterolemic agent commercially available that has found wide patient acceptance.
In light of the enormity of this problem, it would be extremely advantageous to provide a hypocholesterolemic agent which effectively lowers serum cholesterol in a human without the attending side effects typically associated with previous hypocholesterolemic agents. Further, it would be advantageous to provide a hypocholesterolemic agent which is effective when administered to a patient in need thereof in a relatively small dose. Another and important advantage is realized by providing a hypocholesterolemic agent which is administered multiple times or once daily, particularly if a slow release formulation is used. It would also be advantageous to provide a hypocholesterolemic agent which is incorporated into a vehicle, such as a multivitamin and mineral tablet, and administered daily to the general population to prophylactically protect the population against hypercholesterolemia. A still further advantage would be realized in providing a hypocholesterolemic agent which is safely, and inexpensively added to foodstuffs intended for consumption by the general population, and thereby provide prophylactic protection against hypercholesterolemia.
Cellular hyperproliferative disorders are generally characterized by the hyperproliferation and incomplete differentiation of cells. For example, in psoriasis vulgaris there is a hyperproliferation of incompletely differentiated cells of the epidermis. Presently, it is not fully understood what causes certain cells to reproduce rapidly when the host has no apparent need for them. Since growing evidence suggests that cellular hyperproliferation is involved with chemically induced carcinogenesis, the inhibition of cellular proliferation may also be an effective tool for prevention of certain cancers. Accordingly, the inhibition of cellular proliferation may be an effective tool for preventing psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several other diseases associated with the hyperproliferation of cells such as chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, or hairy cell leukemia, or proliferative diseases of retinal cells, for example. In light of the relation between the hyperproliferation of cells and several diseases, it would be extremely advantageous to provide an antiproliferation agent which effectively inhibits cellular hyperproliferation in a human with little or no side effects. Further, it would be beneficial to have an antiproliferative agent which is effective when administered to a patient in need thereof in a relatively small dose. Another and important advantage is realized by providing an antiproliferative agent which may be administered once daily. It would also be advantageous to provide an antiproliferative agent which is incorporated into a vehicle, such as a multivitamin and mineral tablet, and administered daily to the general population to prophylactically protect the population against cellular hyperproliferation. A still further advantage would be realized in providing an antiproliferative agent which is safely, and inexpensively added to foodstuffs intended for consumption by the general population, and thereby provide prophylactic protection against the disease typically associated the with hyperproliferation of cells.
Considering the morbidity and mortality created by both of the above condition, i.e., hypercholesterolemia, and the hyperproliferation of cells, it would be extremely advantageous to provide one agent which prevented or treated both conditions simultaneously. Further, since both conditions affect the general population, it would be advantageous to provide a sustained release preparation, such as a multivitamin and mineral tablet which could be administered to prevent these conditions in the general populations. It would also be of benefit to provide a multivitamin and mineral preparation which contained agents which acted synergistically to prevent or treat hypercholesterolemia and the hyperproliferation of cells.
SUMMARY OF THE INVENTION
One aspect of the invention is directed to a method for the prevention and treatment of hypercholesterolemia. A further aspect of the present invention is directed to a method for the prevention and treatment of cellular hyperproliferation. According to this method, an animal is administered a pharmaceutical formulation including a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof. The animal is preferably a human. The pharmaceutical formulation may be a tablet, capsule, suspension, or solution. The pharmaceutical formulation may be administered by mouth or by injection. The pharmaceutically acceptable salt is preferably selected from the groups consisting of calcium glucarate, sodium glucarate, potassium hydrogen glucarate, and magnesium glucarate.
In accordance with a preferred embodiment, a human is administered daily a sustained release pharmaceutical formulation including from about 200 mg to about 8,000 mg of glucaric acid or a pharmaceutical acceptable salt thereof. In combination with the glucaric acid the pharmaceutical formulation also includes a multiplicity of vitamins, minerals and micronutrients. The preparation is intended as prophylactic protection against the onset of hypercholesterolemia and cellular hyperproliferation.
As an alternative to the above preferred embodiment, a method is provided for the prevention of hypercholesterolemia and/or cellular hyperproliferation in a population of humans and animals. The method provides for adding to a selected foodstuff a predetermined amount of glucaric acid or a pharmaceutical acceptable salt thereof, and thereafter, providing a sufficient quantity of the foodstuff to the population of humans and animals such that the humans and animals ingest a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention provides a formula and method for the treatment of hypercholesterolemia and cellular hyperproliferation. More specifically, the present invention provides a method for administering a formula including glucaric acid or a pharmaceutically acceptable salt thereof for the prevention and treatment of hypercholesterolemia and cellular hyperproliferation in humans and animals. It has been determined that glucaric acid, and the pharmaceutically acceptable salts thereof, significantly lower the total level of serum cholesterol and LDL in animals when administered in therapeutic amounts while simultaneously inhibiting cellular hyperproliferation. It is intended that glucaric acid or a pharmaceutically acceptable salt thereof is employed alone or in combination with other medicinal agents for the prevention and treatment of hypercholesterolemia and/or cellular hyperproliferation.
D-Glucaric acid (glucaric acid) is a six-carbon, straight-chain dicarboxylic acid and is sometimes referred to as D-saccharic acid. Chemically, a schematic formula for D-glucaric acid is COOH--(CHOH)4 --COOH. The salts of D-glucaric acid (glucaric acid) are referred to as D-glucarates (glucarates), e.q., calcium glucarate, sodium glucarate, magnesium glucarate, and potassium hydrogen glucarate.
Glucaric acid and the salts thereof are normal metabolic products in mammals. In both human and rat liver (5) as well as skin (6) glucuronic acid was found to be enzymatically oxidized to glucaric acid. Glucaric acid is the sole end product of the glucuronic acid pathway in guinea pigs and primates (7). Significant interindividual differences have been reported (8) in normal healthy populations. It was observed (9) that the urinary excretion of glucaric acid in cancer patients and tumor-bearing rats was significantly lower than in healthy controls. In mice with experimental tumors and in cancer patients, uninvolved liver tissue was found to have a lowered glucaric acid level (7). Further, studies have shown that cancerous tissues lack the glucaric acid-synthesizing system (7).
The physiological function of glucaric acid/glucarate remains unclear, although it appears to be an important carbohydrate for cell viability and homeostasis. It is not known if glucaric acid is an essential nutrient for normal subjects. Some plants have been analyzed as identifiable sources rich in glucaric acid (10, 11). Recently glucaric acid/glucarate have been found in cruciferous vegetables (12). Glucaric acid/glucarate content is high in young seedlings and sprouts but low in respective seeds (13). Glucaric acid/glucarates are generally non-toxic, and no adverse effects have been observed from prolonged feeding of potassium hydrogen glucarate to rats (14, 15) or calcium glucarate to rats (16) and mice (17).
In accordance with one important aspect of the present invention, a medicament is provided including therapeutic amounts of glucaric acid or a pharmaceutically acceptable salt thereof useful in the treatment and prevention of hypercholesterolemia cellular and hyperproliferation. With respect to hyperproliferation, the present inventors have determined that, by administering therapeutic amounts of glucaric acid/glucarate, total serum cholesterol could be significantly reduced. Studies with this compound demonstrated that HDL, LDL, and VLDL were reduced and, most significantly, serum LDL was reduced. Further, studies have shown that glucarates are generally non-toxic and cause little or no side effects in the individual being treated.
With respect to the antiproliferative effects of glucaric acid, the present inventors have determined that glucaric acid inhibits cellular hyperproliferation in animals. Since cellular hyperproliferation is related not only to the development of certain cancers but also other diseases, e.g., psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several proliferative disorders, it is believed that the use of glucarates for this purpose would be a significant departure from prior method of preventing or treating diseases associated with cellular hyperproliferation.
In accordance with one aspect of the present invention, a method is provided wherein an individual in need thereof is administered a pharmaceutical formulation including a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof. The inventive method is intended to reduce cholesterol in those individuals suffering from hypercholesterolemia and to inhibit cellular hyperproliferation in those individuals in need thereof. Further the formulation and method is intended to prevent the onset of hypercholesterolemia and/or cellular hyperproliferation in those individuals at risk of developing it. The present inventors have demonstrated that glucarates significantly lower total serum cholesterol in rats, and it is believed that this therapeutic effect will also be observed in humans. Moveover, the present inventors have also demonstrated that glucarates inhibit cellular proliferation. It is intended that this discovery be applied beneficially to treat those individuals suffering from cellular hyperproliferation disorders.
Glucaric acid or glucarates may be compounded in numerous acceptable pharmaceutical formulations. Preferable pharmaceutical formulations include tablets, capsules, insuflations, syrups, suspensions, solutions, suppositories, injections, and any sustained release preparation thereof. More preferable, the compound is incorporated into a sustained release tablet or capsule which will provide a hypocholesterolemic and antiproliferative therapeutic effect for the longest possible duration. Thus, the individual receives the maximum benefit from the compound, and patient compliance is increased because the dosage form is administered daily. Injections which are useful in the practice of the present invention include intravascular (e.g., intravenous or intraarterial) subcutaneous, intramuscular, intralymphatic, intraperitoneal, and intrapleural. The most preferable route of the administration for an injection is, however, intravenous.
The pharmaceutical formulation administered to the individual in need thereof preferably includes a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof. Preferably the individual is administered daily from about 10 mg to about 16,000 mg of glucaric acid or a pharmaceutically acceptable salt thereof per day compounded as a single or divided dose. More preferably the individual is administered from about 200 mg to about 8,000 mg per day.
The preferred pharmaceutically acceptable salt of glucaric acid includes any salt of glucaric acid which is both non-toxic and does not substantially diminish the therapeutic effect of the compound. For example, preferred pharmaceutically acceptable salts of glucaric acid include calcium glucarate, sodium glucarate, magnesium glucarate, and potassium hydrogen glucarate. More preferably, however, the pharmaceutical formulation includes potassium hydrogen glucarate and/or calcium glucarate.
In accordance with a further aspect of the invention, glucaric acid and/or glucarate is incorporated as a hypocholesterolemic or antiproliferative agent into nutritional compositions containing vitamins, minerals and/or other micronutrients, e.g., a multivitamin and mineral preparation. Preferably, the glucarate moiety acts as a carrier for minerals such as calcium and potassium. According to this embodiment of the invention, glucarates are included in therapeutic, non-toxic, amounts in a multivitamin supplement as a preventive measure to protect the general population against the onset of hypercholesterolemia and/or cellular hyperproliferation. Such formulas may be prepared according to manufacturing techniques well know in the pharmaceutical art, and in a variety of dosage forms, such as, tablets, capsules, and liquids or sustained release formulations thereof.
According to a further aspect of the invention, glucaric acid and/or glucarates are incorporated in therapeutic amounts into foodstuffs and are consumed by the general population. Presently, many foodstuffs are enriched by the addition of vitamins and mineral supplements, for example, breads, cereals, milk and fruit juices. Glucarates may be added to these products in the same conventional manner in which vitamins or minerals are added to enrich foods. For example, calcium glucarate or potassium hydrogen glucarate may be added to a food product, thereby advantageously providing both a mineral supplement, e.g., calcium and potassium, and prophylactic protection against the onset of hyperproliferative diseases and hypercholesterolemia. Accordingly, the further enrichment of these products with glucaric acid and/or a glucarate will advantageously provide the consuming public with an inexpensive, safe, and convenient alternative for preventing the onset of hyperproliferative diseases and hypercholesterolemia.
As indicated herein above, glucarates are safe, effective hypocholesterolemic and antiproliferation agents. In accordance with one aspect of this invention, glucarate is preferably utilized or administered in combination with a multivitamin and mineral formulation. Preferably, such a formulation is administered as a single sustained release dose.
The following examples are presented to illustrate preferred embodiments of aspects of the present invention but are not intended to limit the scope of the invention unless otherwise specifically so stated in the claims appended hereto.
EXAMPLE 1 Hypocholesterolemic and Antiproliferative Properties of Glucarate-Containing Nutritional Compositions
Calcium D-glucarate was incorporated to the AIN-76A diet (18, 19) at the concentration of 17.5 or 35 mmol/kg diet with no changes in the level of any essential micronutrient. Specifically there was no change in the level of calcium and phosphorus. The AIN-76A or glucarate-containing AIN-76A diets were fed ad libitum to female Sprague-Dawley rats beginning at 40 days of age. Food intake and body weight were monitored periodically. There was no statistically significant difference in food intake or weight gain. DNA labeling indices were measured in 55-day-old rats. Four animals from each dietary group were injected at 9:00 a.m. with a single intraperitoneal dose of [3 H-methyl]thymidine (1.0 μCi/g body weight; specific activity 88 Ci/mmol (Amersham, Arlington Heights, IL) Animals were fasted overnight before they were injected with [3 H-methyl]thymidine. The animals were sacrificed one hour after injection. Colons and small intestines were removed and processed for histology, followed by autoradiography using standard procedures (20). At least 10 and at most 20 complete longitudinal sections of full crypts were evaluated per animal for number and position of labeled cells and number of cells along the crypt columns. Labeling indices for whole crypt height, mean position of the uppermost labeled cells and crypt height were determined for each dietary group.
Remaining animals were sacrificed after 8 weeks on their respective diets. Animals were fasted overnight before they were sacrificed. All animals were killed between 9:00 and 11:00 a.m. to minimize potential diurnal variations. The blood serum was obtained from rats and analyzed for their total cholesterol, triglycerides and lipoprotein cholesterol (21). The test methodologies, all run on a Roche Cobas Mira according to the procedure recommended by manufacturer, were as follows. Total cholesterol was assayed using a sequential enzymatic reaction forming a quinoneimmine dye in one step. Triglycerides in serum were hydrolyzed by lipase to free fatty acids and glycerol to form red chromogen. HDL was separated by isoelectric-polyanionic precipitation of LDL, using phosphotungstate as precipitation reagent. HDL cholesterol (HDL-C) was then assayed as described above for total cholesterol. LDL cholesterol (LDL-C) and VLDL cholesterol (VLDL-C) were calculated using the following formulas: VLDL=Triglycerides/5; LDL-C=Total cholesterol-(VLDL-C+HDL-C). These formulas are from human medicine and are not considered valid at triglyceride levels>400 mg/dl). The data obtained is summarized in tables 1-3 below.
              TABLE 1                                                     
______________________________________                                    
Effect of Dietary Glucarate on Serum Cholesterol                          
Levels in Female Sprague-Dawley Rats.sup.a                                
                 Glucarate-Containing AIN-76A                             
          AIN-76A  17.5 mmol/kg                                           
                              35 mmol/kg                                  
______________________________________                                    
Total cholesterol                                                         
            110.8 ± 2.7                                                
                       100.3 ± 4.0.sup.b                               
                                  95.2 ± 3.7.sup.c                     
Total Triglycerides                                                       
             56.7 ± 4.8                                                
                        54.7 ± 3.5                                     
                                  51.4 ± 4.1                           
HDL-C.sup.d  87.3 ± 3.6                                                
                        82.9 ± 3.9                                     
                                  79.8 ± 3.4                           
LDL-C.sup.e  9.6 ± 0.9                                                 
                        6.7 ± 1.3                                      
                                   6.6 ± 0.9.sup.f                     
VLDL-C.sup.g                                                              
             10.7 ± 0.9                                                
                        10.7 ± 0.7                                     
                                   9.3 ± 0.7                           
______________________________________                                    
 .sup.a Each value is the mean (mg/dl) ± S.E., n = 9 per group.        
 .sup.b Significantly different from the AIN76A value: 10% reduction,     
 p<0.05.                                                                  
 .sup.c Significantly different from the AIN76A value: 14% reduction,     
 p<0.002.                                                                 
 .sup.d HDLC = high density lipoprotein cholesterol.                      
 .sup.e LDLC = low density lipoprotein cholesterol.                       
 .sup.f Significantly different from the AIN76A value: 30% reduction,     
 p<0.05.                                                                  
 .sup.g VLDLC = very low density lipoprotein cholesterol.                 
As shown in the Table 1 above, dietary glucarate significantly and in a dose dependent fashion reduced serum levels of total cholesterol. The LDL cholesterol reduction by glucarate (35 mmol/kg diet) was also significant. There were no significant differences in triglyceride, HDL-C or VLDL-C levels.
Study of cytokinetics of colonic and small intestine mucosa in the two dietary groups (Table 2) revealed that the rats fed the glucarate containing AIN-76A diet (35 mmol/kg) had significantly lower values for labeling indices and position of the uppermost labeled cells than the corresponding values for the AIN-76A control group. There was no significant difference in colonic crypt height.
              TABLE 2                                                     
______________________________________                                    
Cytokinetics of Colonic and Small Intestine                               
Mucosa in 55-Day-Old Female Sprague-Dawley Rats                           
Fed AIN-76A and Glucarate-Containing AIN-76A Diets.sup.a                  
Colon               Small Intestine                                       
              AIN-76A +           AIN-76A +                               
AIN-76A       Glucarate.sup.b                                             
                        AIN-76A   Glucarate.sup.b                         
______________________________________                                    
Crypt   33.1 ± 0.6                                                     
                  32.7 ± 0.6                                           
                            81.4 ± 1.3                                 
                                    90.9 ± 1.4                         
column                                                                    
height                                                                    
(cells)                                                                   
Labeling                                                                  
         4.4 ± 0.5                                                     
                   2.8 ± 0.2.sup.c                                     
                             9.4 ± 0.3                                 
                                     7.1 ± 0.4.sup.d                   
index                                                                     
(per crypt                                                                
column)                                                                   
Highest  6.1 ± 0.7                                                     
                   5.1 ± 0.6.sup.c                                     
                            19.7 ± 1.5                                 
                                    14.8 ± 1.6.sup.e                   
labeled                                                                   
cell                                                                      
position                                                                  
______________________________________                                    
 .sup.a Mean ± S.E.                                                    
 .sup.b 35 mmol/kg diet.                                                  
 .sup.c 36% reduction, p<0.005.                                           
 .sup.d 25% reduction, p<0.0005.                                          
 .sup.e p< 0.025.                                                         
EXAMPLE 2 Effect of Dietary Glucarate on Azoxymethane-Induced Colon Tumorigenesis
Six week-old male Sprague-Dawley rats received a single subcutaneous injection of azoxymethane (15mg/kg body weight) (22). Rats were fed normal chow diets containing 140 mmol/kg of either calcium glucarate or calcium gluconate (negative calcium control) beginning 1 week before carcinogen administration. Animals were sacrificed 8 months post-carcinogen treatment and evaluated for the presence of tumors.
                                  TABLE 3                                 
__________________________________________________________________________
Inhibition of Azoxymethane-Induced Colon                                  
Tumorigenesis by Dietary Glucarate                                        
Rats with Tumors (%)    Tumors per Rat                                    
      No. of                                                              
          Small         Small                                             
Treatment                                                                 
      Rats                                                                
          Intestine                                                       
               Colon                                                      
                   Total                                                  
                        Intestine                                         
                              Colon Total                                 
__________________________________________________________________________
Calcium                                                                   
      17  2(11.7)                                                         
               8(47.0)                                                    
                   10(58.8)                                               
                        0.12 ± 0.10                                    
                              0.53 ± 0.05                              
                                    0.65 ± 0.07                        
Gluconate.sup.a                                                           
(Control)                                                                 
Calcium                                                                   
      16  0    1(6.2).sup.b                                               
                   1(6.2).sup.b                                           
                        0     0.06 ± 0.01.sup.c                        
                                    0.06 ± 0.01.sup.c                  
Glucarate.sup.a                                                           
__________________________________________________________________________
 .sup.a 140 mmol/kg diet.                                                 
 .sup.b Significantly different from control group: p<0.005.              
 .sup.c Significantly different form control group: p<0.05.               
As shown in Table 3, dietary glucarate (140 mmol/kg diet) markedly inhibited azoxymethane-induced tumor±genesis in both the small intestine and colon of the rat. There was no significant difference in tumor incidence or multiplicity between rats fed normal chow and the same chow with the calcium gluconate supplement of 140 mmol/kg. The calcium content itself, increased by 0.56% in the calcium glucarate or gluconate supplemented diets, had no effect on rat colon tumorigenesis. It was previously shown (23) that calcium gluconate inhibits colon carcinogenesis only when high fat diets are fed to rats.
Thus, it is demonstrated that preparations containing glucaric acid significantly reduce serum cholesterol levels without increasing the risk of colon cancer. This appears due to glucarate's surprising antiproliferative effects.
EXAMPLE 3 Vitamin and Mineral Mixtures
The contents of the AIN-76 Mineral Mixture and the AIN-76A Vitamin Mixture are shown in Tables 4 and 5, respectively. These mineral and vitamin mixtures, known from the prior art, were used to prepare the AIN-76A diet used as control diet in Example 1.
              TABLE 4                                                     
______________________________________                                    
AIN-76 Mineral Mixture.sup.a                                              
Ingredient            g/kg mixture                                        
______________________________________                                    
Calcium phosphate, dibasic (CaHPO.sub.4)                                  
                      500.00                                              
Sodium chloride (NaCl)                                                    
                      74.00                                               
Potassium citrate, monohydrate                                            
                      220.00                                              
(K.sub.3 C.sub.6 H.sub.5 O.sub.7.H.sub.2 O)                               
Potassium sulfate (K.sub.2 SO.sub.4)                                      
                      52.00                                               
Magnesium oxide (MgO) 24.00                                               
Manganum carbonate (43-48% Mn                                             
                      3.50                                                
Ferric citrate (16-17% Fe)                                                
                      6.00                                                
Zinc carbonate (70% ZnO)                                                  
                      1.60                                                
Cupric carbonate (53-55% Cu)                                              
                      0.30                                                
Potassium iodate (KIO.sub.3)                                              
                      0.01                                                
Sodium selenite (Na.sub.2 SeO.sub.3.5H.sub.2 O)                           
                      0.01                                                
Chromium potassium sulfate                                                
                      0.55                                                
(CrKSO.sub.4.12H.sub.2 O)                                                 
Sucrose, finely powdered                                                  
                      118.00                                              
______________________________________                                    
 .sup.a To be used at 3.5% of the diet (Journal of Nutrition 107:1340-1348
 1977).                                                                   
              TABLE 5                                                     
______________________________________                                    
AIN-76 Vitamin Mixture.sup.a                                              
Vitamin               g/kg mixture                                        
______________________________________                                    
Thiamine.HCl          0.60                                                
Riboflavin            0.60                                                
Pyridoxine.HCl        0.70                                                
Niacin                3.00                                                
Calcium Pantothenate  1.60                                                
Folic acid            0.20                                                
D-Biotin              0.02                                                
Vitamin B.sub.12 (0.1%)                                                   
                      1.00                                                
Retinyl palmitate (500,000 U/g)                                           
                      0.80                                                
d1-α-Tocopherol acetate (500 U/g)                                   
                      10.00                                               
Cholecalciferol (400,000 U/g)                                             
                      0.25                                                
Menadione sodium bisulfite                                                
                      0.08                                                
Sucrose, finely powdered                                                  
                      981.15                                              
______________________________________                                    
 .sup.a To be used at 1% of diet (Journal of Nutrition 107:1340-1348, 1977
 110:1726, 1980).                                                         
EXAMPLE 4 Mineral Formulas With Glucarate
The contents of four mineral formulas containing glucarate are shown in Table 6. These formulas were used to prepare the modified AIN-76A diets used as experimental diets in Example 1 (formulas 1 and 2) and Example 6 (formulas 3 and 4).
                                  TABLE 6                                 
__________________________________________________________________________
Glucarate-Containing Mineral Formulas.sup.a                               
                    g/kg mixture                                          
Ingredient          Formula 1                                             
                          Formula 2                                       
                                Formula 3                                 
                                      Formula 4                           
__________________________________________________________________________
Calcium phosphate, dibasic (CaHPO.sub.4)                                  
                    366.00                                                
                          433.00                                          
                                500.00                                    
                                      500.00                              
Calcium D-glucarate (CaC.sub.6 H.sub.8 O.sub.8.3.5H.sub.2 O)              
                    300.00                                                
                          150.00.sup.c                                    
                                --    --                                  
Sodium chloride (NaCl)                                                    
                    74.00 74.00 74.00 74.00                               
Potassium citrate, monohydrate                                            
                    --    110.00                                          
                                100.00                                    
                                      168.00                              
(K.sub.3 C.sub.6 H.sub.5 O.sub.7.H.sub.2 O)                               
Potassium phosphate dibasic (K.sub.2 HPO.sub.4)                           
                    172.00                                                
                          86.00 --    --                                  
Potasium hydrogen Dglucarate                                              
                    --    --    238.00.sup.b                              
                                      119.00.sup.c                        
(KC.sub.6 H.sub.7 O.sub.8)                                                
Potassium sulfate (K.sub.2 SO.sub.4)                                      
                    52.00 52.00 52.00 52.00                               
Magnesium oxide (MgO)                                                     
                    24.00 24.00 24.00 24.00                               
Magnesium carbonate (43-48% Mn)                                           
                    3.50  3.50  3.50  3.50                                
Ferric citrate (16-17% Fe)                                                
                    6.00  6.00  6.00  6.00                                
Zinc carbonate (70% ZnO)                                                  
                    1.60  1.60  1.60  1.60                                
Cupric carbonate (53-55% Cu)                                              
                    0.30  0.30  0.30  0.30                                
Potassium iodate (KIO.sub.c)                                              
                    0.01  0.01  0.01  0.01                                
Sodium selenite (Na.sub.2 SeO.sub.3.5H.sub.2 O)                           
                    0.01  0.01  0.01  0.01                                
Chromium potassium sulfate                                                
                    0.55  0.55  0.55  0.55                                
(CrKSO.sub.4.12H.sub.2 O)                                                 
Sucrose, finely powdered                                                  
                    --    59.00 --    51.00                               
__________________________________________________________________________
 .sup.a To be used at 3.5% of the diet.                                   
 .sup.b 34 mmoles of glucarate per kg diet.                               
 .sup.c 17 mmoles of glucarate per kg diet.                               
EXAMPLE 5 Antiproliferative Effect of Nutritional Formulas Containing glucarate
Two modified AIN-76A diet at the concentration of 17 or 34 mmol/kg diet as described in Examples 1 and 4. Specifically, 35 g of the glucarate-containing mineral Formula 1 or 2 (see Table 6) and 10 g of the AIN-76A vitamin mixture (see Table 5) were used per 1 kg AIN-76A diet. Two other experimental diets were prepared by simply supplementing the AIN-76A diet with 70 mmol/kg diet of calcium D-glucarate or calcium 1-tartrate (negative calcium control). Female virgin Sprague-Dawley rats were fed the AIN-76A diet, the same diet plus calcium D-glucarate or calcium L-tartrate, or the modified AIN-76A diets beginning at 40 days of age. After 4 weeks on their respective diets the rats were sacrificed and DNA labeling indices were measured as described in Example 1.
As shown in Table 7, when calcium D-glucarate was incorporated into a mineral composition at the concentration of 34 mmol/kg diet, the DNA synthesis-reducing effect of this formula on the mammary gland epithelium was 3.5-4 times greater than that of the 2-fold higher concentration (70 mmol/kg diet) of calcium D-glucarate used simply as the additive. This result is unexpected and proves the benefit of use of glucarate as a component of mineral and vitamin formulas. Calcium alone had some effect on the mammary gland and colon epithelia but not on the urinary bladder epithelium.
                                  TABLE 7                                 
__________________________________________________________________________
Effect of Dietary Glucarate on DNA Labeling Index in Female Virgin        
Sprague-Dawley Rats                                                       
          Content    Labeling Index (% or per colon crypt).sup.a          
          (mmol/kg diet)                                                  
                     Mammary Gland        Urinary                         
Diet      Glucarate                                                       
                Calcium                                                   
                     Buds   Ducts  Colon  Bladder                         
__________________________________________________________________________
AIN-76A   None  130  19.97 ± 1.25.sup.a                                
                            13.42 ± 1.19                               
                                   11.12 ± 0.89                        
                                          0.51 ± 0.12.sup.a            
AIN-76A + None  200  15.27 ± 0.66                                      
                             7.60 ± 0.57                               
                                    8.21 ± 1.01                        
                                          0.36 ± 0.08.sup.a            
Ca Tartrate                                                               
AIN-76 A +                                                                
          70    200   2.85 ± 0.90                                      
                             0.57 ± 0.15                               
                                    4.58 ± 0.36.sup.a                  
                                          0.32 ± 0.04.sup.a            
Ca Glucarate                                                              
Modified AIN-76A                                                          
          34    130   0.81 ± 0.15                                      
                             0.24 ± 0.10                               
                                    4.19 ± 0.54.sup.a                  
                                          0.08 ± 0.04                  
with glucarate                                                            
__________________________________________________________________________
 .sup.a Mean ± Student's ttests were performed in all possible diet    
 comparisons. For all comparisons but those marked with asterisks, the    
 differences were significant (the pvalues ranged from 0.0005 to 0.025).  
EXAMPLE 6 Hypocholesterolemic effect of Glucarate-Containing Nutritional Formulas
A normal fat diet (pelleted corn starch AIN-76A diet) and a high fat diet containing 5% and 20% fat, respectively, were prepared as described in the prior art (Dyets, Inc. 1981/1988 catalog: Experimental Diets & Ingredients for Laboratory Animals). Two high fat diets were prepared by incorporating potassium hydrogen D-glucarate at the concentration of 17 or 34 mmol/kg diet using the mineral formulas 3 and 4 as described in Example 4 (see Table 6). Female virgin Sprague-Dawley rats were fed these experimental diets or control diets for 4 weeks beginning at 44 days of age. The rats were sacrificed and the blood was assayed for total cholesterol, total triglycerides, HDL-C, LDL-C and VLDL-C as described in Example 1. The results are shown in Table 8.
The hypercholesterolemic high fat diet increased the serum levels of total cholesterol and LDL cholesterol 1.2-fold and 2.3-fold, respectively. However, the increased total cholesterol and LDL cholesterol levels were reduced 12% (p<0.05) and 35% (0.02) respectively by using the glucarate mineral Formula 3 of Example 4 (34 mmol glucarate per kg high fat diet).
                                  TABLE 8                                 
__________________________________________________________________________
Effect of Dietary Glucarate on Serum Cholesterol Levels.sup.a in Female   
Sprague-Dawley Rats                                                       
Fed Hypercholesterolemic Diets                                            
      Glucarate                                                           
              Fat                                                         
                 Total  Total                                             
Diet  (mmol/kg diet)                                                      
              (%)                                                         
                 Cholesterol                                              
                        TriGlycerides                                     
                               HDL-C.sup.b                                
                                     LDL-C.sup.c                          
                                           VLDL-C.sup.d                   
__________________________________________________________________________
NFD.sup.e                                                                 
      None     5  87.0 ± 5.6                                           
                        26.8 ± 4.8                                     
                               71.8 ± 7.7                              
                                     10.0 ± 2.2                        
                                           5.1 ± 1.1                   
HFD.sup.f                                                                 
      None    20 105.6 ± 4.5                                           
                        31.0 ± 2.4                                     
                               76.1 ± 3.8                              
                                     23.3 ± 1.4                        
                                           6.1 ± 0.4                   
HFD with                                                                  
      34      20  92.4 ± 4.1.sup.g                                     
                        25.7 ± 1.7                                     
                               72.3 ± 3.3                              
                                     15.1 ± 1.4.sup.h                  
                                           5.0 ± 0.3                   
Glucarate                                                                 
HFD with                                                                  
      17      20 101.3 ± 5.4                                           
                        32.1 ± 3.7                                     
                               73.4 ± 3.1                              
                                     21.6 ± 2.1                        
                                           6.3 ± 0.8                   
glucarate                                                                 
__________________________________________________________________________
 .sup.a Each value is the mean (mg/dl) ± S.E.; n = 7.                  
 .sup.b HDLC = high density lipoprotein cholesterol.                      
 .sup.c LDLC = low density lipoprotein cholesterol.                       
  .sup.d VLDLC = Very low density lipoprotein cholesterol.                
 .sup.e NFD = normal fat diet (corn starch AIN76A diet; J. Nutr. 107:1341,
 1977; 110:1726, 1980) containing 5% corn oil.                            
 .sup.f HDF = high fat diet containing 20% corn oil.                      
 .sup.g Significantly different from the high fat diet value: 12% reductio
 (p<0.05).                                                                
 .sup.h Significantly different from the high fat diet value: 35% reductio
 (p<0.02).                                                                
EXAMPLE 7 Pharmaceutical Formulas Containing Glucarate
The chemical contents and vitamin and mineral contents of two pharmaceutical formulas containing glucarate are shown in Table 9 and 10, respectively. Both formulas contain magnesium and potassium and vitamin D. The calcium to phosphorus ratios remain within the physiologically required range of 1.3 to 1 or 1 to 1. Calcium D-glucarate is used as a source of glucarate.
              TABLE 9                                                     
______________________________________                                    
Chemical Content of Two Pharmaceutical                                    
Formulas with Glucarate                                                   
                 Amount.sup.b                                             
Active Ingredient  Formula 1.sup.c                                        
                                  Formula 2.sup.d                         
______________________________________                                    
Cholecalciferol    1.25    μg  1.25  μg                             
Calcium Phosphate, dibasic                                                
                   374.15  mg     374.15                                  
                                        mg                                
(CaHPO.sub.4)                                                             
Calcium D-glucarate                                                       
                   320.20  mg     320.20                                  
                                        mg                                
(CaC.sub.6 H.sub.8 O.sub.8 4 H.sub.2 O)                                   
Potassium phosphate, dibasic                                              
                   363.50  mg     169.00                                  
                                        mg                                
(K.sub.2 HPO.sub.4)                                                       
Magnesium oxide    83.90   mg     82.90 mg                                
(MgO)                                                                     
______________________________________                                    
 .sup.a For vitamin and mineral content see Table 10.                     
 .sup.b Per tablet, capsule, caplet or wafer.                             
 .sup.c Calcium to phosphorus ratio 1 to 1.                               
 .sup.d Calcium to phosphorus ratio 1.3 to 1.                             
                                  TABLE 10                                
__________________________________________________________________________
Vitamin and Mineral Content of Two Pharmaceutical Formulas                
with Glucarate.sup.a                                                      
          Formula 1.sup.b                                                 
                       Formula 2.sup.c                                    
Vitamin or Mineral                                                        
          Amount.sup.d                                                    
               % U.S. RDA.sup.e                                           
                       Amount.sup.d                                       
                            % U.S. RDA.sup.e                              
__________________________________________________________________________
Vitamin D 50 IU                                                           
               12.5    50 IU                                              
                            12.5                                          
Calcium   150                                                             
             mg                                                           
               12.5    150                                                
                          mg                                              
                            12.5                                          
Phosphorus                                                                
          150                                                             
             mg                                                           
               12.5    115                                                
                          mg                                              
                            9.6                                           
Magnesium 50 IU                                                           
               12.5    50 mg                                              
                            12.5                                          
Potassium 163                                                             
             mg                                                           
               N.D..sup.f                                                 
                       76 mg                                              
                            N.D..sup.f                                    
Glucarate 209                                                             
             mg                                                           
               N.D..sup.f                                                 
                       209                                                
                          mg                                              
                            N.D..sup.f                                    
__________________________________________________________________________
 .sup.a For chemical content see Table 9.                                 
 .sup.b Calcium to phosphorus ratio 1 to 1.                               
 .sup.c Calcium to phosphorus ratio 1.3 to 1.                             
 .sup.d Per tablet, capsule, caplet or wafer. The highest recommended dose
 (Recommended Dietary Allowances, 10th Edition, NAP, Washington, D.C.     
 1989).                                                                   
 .sup.e U.S. Recommended Daily Allowances has not been established.       
 .sup.f N.D. = Not Determined.                                            
EXAMPLE 8 A Vitamin and Mineral Supplement with Glucarate
Table 11 shows the vitamin and mineral content of a pharmaceutical formula with glucarate provided in the form of potassium hydrogen D-glucarate.
              TABLE 11                                                    
______________________________________                                    
A Vitamin and Mineral Pharmaceutical Formula with Glucarate               
Vitamin or Mineral                                                        
                Amount.sup.a                                              
                         % U.S. RDA.sup.b                                 
______________________________________                                    
Vitamin D.sup.c  50 IU   12.5                                             
Calcium.sup.d   150 mg   12.5                                             
Phosphorus.sup.e                                                          
                115 mg   12.5                                             
Magnesium.sup.f  50 mg   12.5                                             
Potassium.sup.g  39 mg   N.D..sup.h                                       
Glucarate.sup.g 209 mg   N.D..sup.h                                       
______________________________________                                    
 .sup.a Per tablet, capsule, caplet or wafer.                             
 .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th
 Edition, NAP, Washington, D.C., 1989).                                   
 .sup.c As cholecalciferol (1.25 μg).                                  
 .sup.d As calcium phosphate, dibasic (510.2 mg).                         
 .sup.e As calcium phosphate, dibasic (see above). Calcium to phosphate   
 ratio 1.3 to 1.                                                          
 .sup.f As magnesium oxide (82.90 mg).                                    
 .sup.g As potassium hydrogen Dglucarate (248.2 mg).                      
 .sup.h N.D. = Not Determined.                                            
EXAMPLE 9 Multi-Vitamin and Multi-Mineral Formula Containing Glucarate
The contents of multi-vitamin and mineral formula with glucarate designed to provide recommended dietary allowances of vitamins, minerals and trace elements, is shown in Table 12. Eight tablets, capsules, caplets or wafers, two of them to be taken at breakfast, lunch, dinner, and supper, provide 100% RDA.
              TABLE 12                                                    
______________________________________                                    
A Multi-Vitamin and Multi-Mineral Formula                                 
with Glucarate                                                            
Vitamin, Mineral                                                          
or Trace Element                                                          
              Amount.sup.a                                                
                          % U.S. RDA.sup.b                                
______________________________________                                    
Vitamin A.sup.c                                                           
              162.5   RE      12.5                                        
Vitamin D.sup.d                                                           
              50.0    IU      12.5                                        
Vitamin E.sup.e                                                           
              1.5     α-TE                                          
                              12.5                                        
Vitamin K     10.0    μg   12.5                                        
Vitamin C     12.0    mg      12.5                                        
Thiamin       0.2     mg      12.5                                        
Riboflavin    225.0   μg   12.5                                        
Niacin.sup.f  2.5     NE      12.5                                        
Vitamin B.sub.6                                                           
              275.0   μg   12.5                                        
Folate        50.0    μg   12.5                                        
Vitamin B.sub.12                                                          
              325.0   ng      12.5                                        
Biotin        12.5    μg   12.5.sup.g                                  
Panthothenic acid                                                         
              875.0   μg   12.5                                        
Calcium.sup.h 150.0   mg      12.5                                        
Phosphorus.sup.i                                                          
              150.0   mg      12.5                                        
Magnesium     50.0    mg      12.5                                        
Iron          3,750.0 μg   12.5                                        
Zinc          1,875.0 μg   12.5                                        
Iodine        25.0    μg   12.5                                        
Selenium      9.5     μg   12.5                                        
Copper        375.0   μg   12.5.sup.g                                  
Manganese     625.0   μg   12.5.sup.g                                  
Fluoride      500.0   μg   12.5.sup.g                                  
Chromium      25.0    μg   12.5.sup.g                                  
Molybdenum    32.0    μg   12.5.sup.g                                  
Potassium.sup.j                                                           
              163.0   mg      N.D..sup.k                                  
Glucarate.sup.l                                                           
              209.0   mg                                                  
______________________________________                                    
 .sup.a Per tablet, capsule, caplet or wafer.                             
 .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th
 Edition, NAP, Washington, D.C., 1989).                                   
 .sup.c 1 Retinol Equivalent (RE) = 1 μg retinol or 6 μg carotene or
 an equivalent amount of a retinoic acid compound.                        
 .sup.d As cholecalciferol. 10 μg cholecalciferol = 400 IU of vitamin D
 .sup.e Tocopherol Equivalent (TE) = 1 mg dtocopherol.                    
 .sup.f 1 Niacin Equivalent (NE) = 1 mg of niacin.                        
 .sup.g The highest estimated safe or adquate dose (ibid.).               
 .sup.h As calcium phosphate, dibasic (374.15 mg) and calcium Dglucarate  
 tetrahydrate (320.2 mg).                                                 
 .sup.i As calcium phosphate, dibasic (see above) and potassium phosphate,
 dibasic (363.50 mg). Calcium to Phosphorus ratio 1 to 1.                 
 .sup.j As potassium phosphate, dibasic (see above).                      
 .sup.k N.D. = Not Determined.                                            
 .sup.l As calcium Dglucarate (see above).                                
EXAMPLE 10 High-Potency Multi-Vitamin and Multi-Mineral Formula Containing Glucarate
The contents of high-potency multivitamin and mineral disease-preventative formula with glucarate is shown in Table 13. Four tablets or packets, each to be taken at breakfast, lunch, dinner and supper, provide shown % RDA of vitamins and minerals.
              TABLE 13                                                    
______________________________________                                    
A High Potency Multi-Vitamin and                                          
Mineral Formula with Glucarate                                            
Vitamin or Mineral                                                        
              Amount.sup.a                                                
                          % U.S. RDA.sup.b                                
______________________________________                                    
Vitamin A.sup.c                                                           
              1,300.0 RE      100                                         
Vitamin D.sup.d                                                           
              400.0   IU      100                                         
Vitamin E.sup.e                                                           
              48.0    α-TE                                          
                              400                                         
Vitamin C     768.0   mg      800                                         
Thiamin       40.0    mg      2500                                        
Riboflavin    4,140.0 μg   230                                         
Niacin.sup.f  40.0    NE      200                                         
Vitamin B.sub.6                                                           
              44.0    mg      2000                                        
Folate        400.0   μg   100                                         
Vitamin B.sub.12                                                          
              41.6    μg   1600                                        
Pantothenic acid                                                          
              56.0    mg      .sup. 800.sup.g                             
Calcium.sup.h 600.0   mg       50                                         
Phosphorus.sup.i                                                          
              600.0   mg       50                                         
Magnesium     200.0   mg       50                                         
Zinc          15.0    mg      100                                         
Selenium      76.0    μg   100                                         
Potassium.sup.j                                                           
              652.0   mg      N.D..sup.k                                  
Glucarate     832.0   mg      N.D..sup.k                                  
______________________________________                                    
 .sup.a Per four tablets or packets.                                      
 .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th
 Edition, NAP, Washington, D.C., 1989).                                   
 .sup.c 1 Retinol Equivalent (RE) = 1 μg retinol or 6μ carotene, or 
 an equivalent amount of a retinoic acid compound.                        
 .sup.d As cholecalciferol. 10 μg cholecalciferol = 400 IU of Vitamin D
 .sup.e Tocopherol Equivalent (TE) = 1 mg dtocopherol.                    
 .sup.f 1 Niacin Equivalent (NE) = 1 mg of niacin.                        
 .sup.g The highest estimated safe or adequate dose (ibid.).              
 .sup.h As calcium phosphate, dibasic (1,496.6 mg) and calcium Dglucarate,
 tetrahydrate, (1,280.0 mg).                                              
 .sup.i As calcium phosphate, dibasic (see above) and potassium phosphate,
 dibasic (1,454.0 mg). Calcium to phosphorus ratio 1 to 1.                
 .sup.j As potassium phosphate, dibasic (see above).                      
 .sup.k N.D. = Not Determined.                                            
 .sup.l As calcium Dglucarate (see above).                                
EXAMPLE 11 Glucarate-Containing Chemically Defined Diet for Enteral Nutrition
The contents of a chemically defined diet with glucarate is shown in Table 14. This is an example of a nutritionally complete, elemental diet for enteral nutrition. Table 15 describes acceptable ranges of these components.
              TABLE 14                                                    
______________________________________                                    
A Chemically Defined Diet with Glucarate                                  
Ingredient       Amount.sup.a                                             
                             % U.S. RDA.sup.b                             
______________________________________                                    
Macroconstituents:                                                        
Amino Acids (Free)                                                        
                 37.1    g                                                
Carbohydrates    407.4   g                                                
(Predisgested)                                                            
Fat              2.6     g                                                
Linoleic acid    2.1     g                                                
Vitamins, Minerals, Electro-                                              
lytes, Trace Elements:                                                    
Vitamin A.sup.c  1300.0  RE      100                                      
Vitamin D.sup.d  400.0   IU      100                                      
Vitamin E.sup.e  12.0    α-TE                                       
                                 100                                      
Vitamin K        80.0    mg      100                                      
Vitamin C        96.0    mg      100                                      
Thiamin          1.6     mg      100                                      
Riboflavin       1.8     mg      100                                      
Niacin.sup.f     20.0    NE      100                                      
Vitamin B.sub.6  2.2     mg      100                                      
Folate           400.0   μg   100                                      
Vitamin B.sub.12 2.6     mg      100                                      
Biotin           100.0   μg   .sup. 100.sup.g                          
Pantothenic acid 7.0     mg      .sup. 100.sup.g                          
Calcium.sup.h    1,200.0 mg      100                                      
Phosphorus.sup.i 1,200.0 mg      100                                      
Magnesium        400.0   mg      100                                      
Iron             30.0    mg      100                                      
Zinc             15.0    mg      100                                      
Iodine           200.0   μg   100                                      
Selenium         75.0    μg   100                                      
Copper           3.0     mg      .sup. 100.sup.g                          
Manganese        5.0     mg      .sup. 100.sup.g                          
Fluoride         1.0     μg   .sup. 100.sup.g                          
Chromium         200.0   μg   .sup. 100.sup.g                          
Molybdenum       250.0   μg   .sup. 100.sup.g                          
Choline          73.3    mg      .sup. N.D..sup.j                         
Sodium           842.4   mg      N.D.                                     
Potassium.sup.k  2,110.0 mg      N.D.                                     
Chloride         1,710.0 mg      N.D.                                     
Acetate          995.0   mg      N.D.                                     
Glucarate.sup.l  3,525.0 mg      N.D.                                     
______________________________________                                    
 .sup.a Per six packets. One packet to be diluted with water to a total   
 standard dilution volume of 300 ml.                                      
 .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th
 Edition, NAP, Washington, D.C., 1989).                                   
 .sup.c 1 Retinol Equivalent (RE) = 1 μg retinol or 6 μg carotene or
 an equivalent amount of a retinoic acid compound.                        
 .sup.d As cholecalciferol. 10 μg cholecalciferol = 400 IU of vitamin D
 .sup.e Tocopherol Equivalent (TE) = 1 mg dtocopherol.                    
 .sup.f 1 Niacin Equivalent (NE) = 1 mg of niacin.                        
 .sup.g The highest estimated safe or adquate dose (ibid.).               
 .sup.h As calcium phosphates.                                            
 .sup.i As calcium and potassium phosphates.                              
 .sup.j N.D. = Not Determined.                                            
 .sup.k As potassium phosphate and potassium hydrogen Dglucarate.         
 .sup.l As potassium hydrogen Dglucarate.                                 
              TABLE 15                                                    
______________________________________                                    
A Chemically Defined Diet with Glucarate                                  
______________________________________                                    
7-15%         by weight of Amino Acids                                    
76-86%        by weight of Carbohydrates                                  
0.4-1.2%      by weight of Fat                                            
0.4-1.0%      by weight of Linoleic acid, and                             
1,200.0-1,800.0                                                           
              RE of Vitamin A                                             
400.0-600.0   IU of Vitamin D                                             
12.0-18.0     α-TE of Vitamin E                                     
80.0-120.0    mg of Vitamin K                                             
96.0-480.0    mg of Vitamin C                                             
1.6-3.2       mg of Thiamin                                               
1.8-3.6       mg of Riboflavin                                            
20.0-40.0     NE of Niacin                                                
2.2-4.4       mg of Vitamin B.sub.6                                       
400.0-800.0   μg of Folate                                             
2.6-5.2       mg of Vitamin B.sub.12                                      
100.0-200.0   μg of Biotin                                             
7.0-14.0      mg of Pantothenic acid                                      
1,000.0-1,200.0                                                           
              mg of Calcium                                               
1,000.0-1,200.0                                                           
              mg of Phosphorus                                            
350.0-400.0   mg of Magnesium                                             
15.0-30.0     mg of Iron                                                  
15.0-22.5     mg of Zinc                                                  
150.0-200.0   μg of Iodine                                             
50.0-150.0    μg of Selenium                                           
2.0-3.0       mg of Copper                                                
2.0-5.0       mg of Manganese                                             
0-4.0         mg of Fluoride                                              
0-200.0       μg of Chromium                                           
0-250.0       μg of Molybdenum                                         
72.0-720.0    mg of Choline                                               
840.0-845.0   mg of Sodium                                                
2,110.0-2,400.0                                                           
              mg of Potassium                                             
1,620.0-1,710.0                                                           
              mg of Chloride,                                             
0-1,000.0     mg of Acetate, and                                          
1,750.0-7,050.0                                                           
              mg of Glucarate.                                            
______________________________________                                    
While the invention is susceptible to various modifications and alternative forms, a specific embodiment thereof has been shown by way of example and was described above in detail. It should be understood, however, that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
The following citations are incorporated in pertinent part by reference herein for the reasons cited above.
1. Sutherlands, N. H. F., Temple, W. A., Nye, E. R. and Herbison, G. P., 1980, Am. J. Clin. Nutr. 33:2581.
2. Barret-Connor, E., Witzmum, J. L. and Holdbrook, M., 1983, Am. J. Epidemiology 117:186.
3. Nigro, N. D., Campbell, R. L., Gantt, J. S. et al., 1977, Cancer Res. 37:3198.
4. Nigro, N. D., Bhadrachri, N. and Chomachai, C., 1973, Dis. Colon Rectum 16:438.
5. Marsh, C. A., 1963, Biochem, J., 87:82.
6. Masaki, H., 1972, Nippon Hifuka Gakkai Zashi, 82:151, 233; Chem. Abstr., 78: 2709b, 27062u.
7, Levvy, G. A. and Conchie, J., 1966, in Dutton, G. J. (ed.), Glucuronic Acid,: Academic Press, New York, p. 301.
8. Mocarelli, P., Brambilla, P., Colombo, L., Marocchi, A., Crespi, C., Tramacere, P., Mondonica, A., 1989, Clin. Chem. 34:2283.
9. Yokoyama, M., Matsuoka, S. and Wakui, A. Recent Adv. Chemother, Proc. Int. congr. Chemother, 14th, 1985, Univ. Tokyo Press, Tokyo, Japan.
10. Kringstad, R. and nordal, A., 1975, Phytochemistry, 14:1868.
11. Elliger, C. A., Lundin, R. E. and Haddon, W. F., 1981, Phytochemistry, 20:1133.
12. Walaszek, Z., Hanausek-Walaszek, M. and Webb, T. E., 1984, Proc. Am. Assoc. Cancer Res.,25:128.
13. Kessler, G., Neufeld, E. F., Feingold, G. S. and Hassid, W., 1961, J. Biol Chem., 236:308.
14. Ambrose, A. M., 1951, J. Am. Pharm, Assoc. 40:277.
15. Carr, C. J., 1947, Proc. Soc. Exptl, Biol. Med. 65:189.
16. Walaszek, Z., Hanausek-Walaszek, M., Minton, J. P. and Webb, T. E., 1986, Carcinogenesis, 7:1463.
17. Walaszek, Z., Hanausek-Walaszek, M., Webb, T. E., 1986, Cancer Lett., 33:25.
18. Ad Hoc Committee on Standards for Nutritional Studies, 1977, J. Nutr., 107:1340.
19. Ad Hoc Committee on Standards for Nutritional Studies, 1980, J. Nutr., 110:1726.
20. Bird, R. P., Schneider, R., Stamp, D. and Bruce, W. R., 1986, Carcinogenesis 7:1657.
21. Lindgren, F. T., 1975, in Perkins, E. G. (ed.) Analysis of Lipids and Lipoproteins, Am. Oil Chemists' Society, Champagne, Il., p. 204.
22. Ward, J. M., 1975, Vet. Pathol. 12:165.
23. Pence, B. C. and Buddingh, F., 1988, Carcinogenesis 9:187.

Claims (12)

What is claimed is:
1. A method for the lowering of cholesterol levels comprising administering to an animal in need thereof a formulation including an effective amount of calcium D-glucarate or potassium hydrogen D-glucarate, said amount being effective for lowering elevated cholesterol levels.
2. The method of claim 1 wherein said animal is a human.
3. The method of claim 1 wherein said formulation is a pharmaceutically acceptable tablet, capsule, caplet, wafer, suspension, or solution.
4. The method of claim 1 wherein the administration is enteral.
5. The method of claim 4 wherein said formulation is a sustained release formulation.
6. The method of claim 5 wherein said administration is once daily as a single dose or several times a day as a divided dose.
7. The method of claim 1 wherein said effective amount is from about 10 mg to about 16,000 mg, daily.
8. The method of claim 1 wherein said effective amount is from about 200 mg to about 8,000 mg, daily.
9. The method of claim 1, comprising administering an effective amount of calcium D-glucarate.
10. The method of claim 1 wherein said pharmaceutically acceptable salt is potassium hydrogen D-glucarate.
11. A method for the lowering of cholesterol levels comprising administering daily to a human in need thereof a sustained release pharmaceutical formulation including from about 200 mg to about 8,000 mg of calcium D-glucarate or potassium hydrogen D-glucarate.
12. The method of claim 11 wherein said sustained release pharmaceutical formulation further includes a multiplicity of vitamins, minerals and micronutrients.
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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1066885A (en) * 1964-07-29 1967-04-26 Zh Tokyo Seikagaku Kenkyukai Therapeutic agent and compositions having the inhibitory action for ª‰-glucuronidase and method of inhibiting ª‰-glucuronidase
US3697287A (en) * 1969-01-28 1972-10-10 Morton Norwich Products Inc Amino acid food composition
NL7712421A (en) * 1976-11-13 1978-05-17 Koehler Valentin PROCESS FOR PREPARING AN AGENT WITH PHARMACEUTICAL AND / OR ANTI-MICROBIAL ACTION.
DE2651947A1 (en) * 1976-11-13 1978-05-18 Koehler Valentin Compsns. contg. glucaric acid or its derivs. - useful as antibacterial and antifungal medicaments, food preservatives, microbicides and disinfectants
US4740373A (en) * 1986-05-27 1988-04-26 Usv Pharmaceutical Corporation Stabilization of multivitamin/trace elements formulations
US4751085A (en) * 1984-08-29 1988-06-14 Gaull Gerald E Human nutritional compositions containing taurine and vitamins and/or minerals
US4845123A (en) * 1985-08-05 1989-07-04 The Ohio State University Reduction in vivo of the inappropriate levels of endogenous and environmental-derived compounds by sustained-release inhibitors of β-g
US4997852A (en) * 1987-08-26 1991-03-05 Ohio State University Research Foundation Method and composition for achieving cancer chemopreventive and chemotherapeutic activity
US5008291A (en) * 1987-08-26 1991-04-16 Ohio State University Research Foundation Method and composition for achieving chemotherapeutic activity
US5010107A (en) * 1987-08-26 1991-04-23 Ohio State University Research Foundation Method and composition for achieving anticarcinogenic activity
WO1991018593A1 (en) * 1990-05-16 1991-12-12 Board Of Regents, The University Of Texas System Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1066885A (en) * 1964-07-29 1967-04-26 Zh Tokyo Seikagaku Kenkyukai Therapeutic agent and compositions having the inhibitory action for ª‰-glucuronidase and method of inhibiting ª‰-glucuronidase
US3697287A (en) * 1969-01-28 1972-10-10 Morton Norwich Products Inc Amino acid food composition
NL7712421A (en) * 1976-11-13 1978-05-17 Koehler Valentin PROCESS FOR PREPARING AN AGENT WITH PHARMACEUTICAL AND / OR ANTI-MICROBIAL ACTION.
DE2651947A1 (en) * 1976-11-13 1978-05-18 Koehler Valentin Compsns. contg. glucaric acid or its derivs. - useful as antibacterial and antifungal medicaments, food preservatives, microbicides and disinfectants
FR2370471A1 (en) * 1976-11-13 1978-06-09 Kohler Valentin Compsns. contg. glucaric acid and derivs. - useful as microbicides and pharmaceuticals
US4751085A (en) * 1984-08-29 1988-06-14 Gaull Gerald E Human nutritional compositions containing taurine and vitamins and/or minerals
US4845123A (en) * 1985-08-05 1989-07-04 The Ohio State University Reduction in vivo of the inappropriate levels of endogenous and environmental-derived compounds by sustained-release inhibitors of β-g
US4740373A (en) * 1986-05-27 1988-04-26 Usv Pharmaceutical Corporation Stabilization of multivitamin/trace elements formulations
US4997852A (en) * 1987-08-26 1991-03-05 Ohio State University Research Foundation Method and composition for achieving cancer chemopreventive and chemotherapeutic activity
US5008291A (en) * 1987-08-26 1991-04-16 Ohio State University Research Foundation Method and composition for achieving chemotherapeutic activity
US5010107A (en) * 1987-08-26 1991-04-23 Ohio State University Research Foundation Method and composition for achieving anticarcinogenic activity
WO1991018593A1 (en) * 1990-05-16 1991-12-12 Board Of Regents, The University Of Texas System Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders

Non-Patent Citations (53)

* Cited by examiner, † Cited by third party
Title
Abou Issa et al., Putative Metabolites Derived from Dietary Combinations of Calcium Glucarate and N (4 hydroxyphenyl) Retinamide Act Synergistically to Inhibit the Induction of Rat Mammary Tumors by 7,12 dimethylbenz a anthracene, Proc. Natl. Acad. Sci. USA, 85:4181 4184 (1988) published in USA. *
Abou-Issa et al., "Putative Metabolites Derived from Dietary Combinations of Calcium Glucarate and N-(4-hydroxyphenyl) Retinamide Act-Synergistically to Inhibit the Induction of Rat Mammary Tumors by 7,12-dimethylbenz[a]anthracene," Proc. Natl. Acad. Sci. USA, 85:4181-4184 (1988) published in USA.
Alberts et al., "Mevinolin: A Highly Potent Competitive Inhibitor of Hydroxymethylglutaryl-coenzyme A Reductase and a Cholesterol-lowering Agent," Proc. Natl. Acad. Sci. USA, 77(7):3957-3961 (1980), published in USA.
Alberts et al., Mevinolin: A Highly Potent Competitive Inhibitor of Hydroxymethylglutaryl coenzyme A Reductase and a Cholesterol lowering Agent, Proc. Natl. Acad. Sci. USA, 77(7):3957 3961 (1980), published in USA. *
Babiak et al., "Effects of Dietary Polyunsaturated and Saturated Fats on Lipoproteins in the Baboon," Atherosclerosis, 57:1-17 (1985), published in Ireland.
Babiak et al., Effects of Dietary Polyunsaturated and Saturated Fats on Lipoproteins in the Baboon, Atherosclerosis, 57:1 17 (1985), published in Ireland. *
Boyland et al., "An Attempt to Prevent the Induction of Bladder Cancer in Dogs with 1→4-Gluco-Saccharolactone," Investigative Urology, 2(5):439-445 (1965), published in USA.
Boyland et al., "Attempted Prophylaxis of Bladder Cancer with 1→4 glucosaccharolactone," British Journal of Urology, 36:563-569 (1964), published in United Kingdom.
Boyland et al., An Attempt to Prevent the Induction of Bladder Cancer in Dogs with 1 4 Gluco Saccharolactone, Investigative Urology, 2(5):439 445 (1965), published in USA. *
Boyland et al., Attempted Prophylaxis of Bladder Cancer with 1 4 glucosaccharolactone, British Journal of Urology, 36:563 569 (1964), published in United Kingdom. *
Bradley, "Effect of a β-Glucuronidase Inhibitor and Methylcholanthrene on the Induction of Bladder Tumors in Rats," the Journal of Urology, 55(5):626-628 (1962), published in USA.
Bradley, Effect of a Glucuronidase Inhibitor and Methylcholanthrene on the Induction of Bladder Tumors in Rats, the Journal of Urology, 55(5):626 628 (1962), published in USA. *
Furuno et al., "Effect of D-Glucarates on Basic Antiobiotic-Induced Renal Damage in Rats," Chemical Abstracts, 84:41 (1976), Abstract No. 115903y, published in USA.
Furuno et al., "Preventive Effect of D-Glucarate against Renal Damage Induced by Kanamycin," Chemical Abstracts, 85:45 (1976), Abstract No. 154048p, published in USA.
Furuno et al., Effect of D Glucarates on Basic Antiobiotic Induced Renal Damage in Rats, Chemical Abstracts, 84:41 (1976), Abstract No. 115903y, published in USA. *
Furuno et al., Preventive Effect of D Glucarate against Renal Damage Induced by Kanamycin, Chemical Abstracts, 85:45 (1976), Abstract No. 154048p, published in USA. *
Garrison and Somer, "Vitamins and Minerals: Their Relationship to Cardiovascular Disease," the Nutrition Desk Reference, Keats Publishing, Inc., New Canaan, Conn., Chapter 14, pp. 172-180 (1985), published in USA.
Garrison and Somer, Vitamins and Minerals: Their Relationship to Cardiovascular Disease, the Nutrition Desk Reference, Keats Publishing, Inc., New Canaan, Conn., Chapter 14, pp. 172 180 (1985), published in USA. *
Iida et al., "2,5-DI-O-Acetyl-D-Glucosaccharo-(1-4), (6-8)-Dilactone, A New Potent β-Glucuronidase Inhibitor," Jap. J. Pharmacol., 15:88-90 (1955), published in Japan.
Iida et al., 2,5 DI O Acetyl D Glucosaccharo (1 4), (6 8) Dilactone, A New Potent Glucuronidase Inhibitor, Jap. J. Pharmacol., 15:88 90 (1955), published in Japan. *
Katayama, "A Study on Prophylaxis for Recurrence of Bladder Tumor," 63(11):951-971 (1972), published in Japan.
Katayama, A Study on Prophylaxis for Recurrence of Bladder Tumor, 63(11):951 971 (1972), published in Japan. *
Kazuo et al., "Studies on Experimental Bladder Tumors. Report 3. Exzymologicl and Histological Study of the Effects of Both β-Glucuronidase Inhibitor and X-Ray Irradiation on Rat BBN Bladder Tumor," Chemical Abstracts, 86:361-362 (1977), Abstract No. 41460u, published in USA.
Kazuo et al., Studies on Experimental Bladder Tumors. Report 3. Exzymologicl and Histological Study of the Effects of Both Glucuronidase Inhibitor and X Ray Irradiation on Rat BBN Bladder Tumor, Chemical Abstracts, 86:361 362 (1977), Abstract No. 41460u, published in USA. *
Levvy, "The Preparation and Properties of β-Glucuronidase. 4. Inhibition by Sugar Acids and Their Lactones," Biochem., 52:464-472 (1952), published in USA.
Levvy, The Preparation and Properties of Glucuronidase. 4. Inhibition by Sugar Acids and Their Lactones, Biochem., 52:464 472 (1952), published in USA. *
Merck Index, p. 240, #1720 Candicidin, published in USA (1982).
Merck Index, p. 240, 1720 Candicidin, published in USA (1982). *
Miyakawa et al., "The Effect of Urinary β-Glucuronidase Inhibitor on the Induction of Bladder Tumors with 2-Acetylaminofluorene in Rats," Investigative Urology, 10(4):256-261 (1973), published in USA.
Miyakawa et al., The Effect of Urinary Glucuronidase Inhibitor on the Induction of Bladder Tumors with 2 Acetylaminofluorene in Rats, Investigative Urology, 10(4):256 261 (1973), published in USA. *
Product Information, Merck, Sharp & Dohme, 1413 (1989), published in USA. *
Rawson et al., "Summation and Future Challenges," In: Inhibition of Tumor Induction and Development, Zedeck and Lipkin, editors, Plenum Press, New York, publishers, Chapter 9, pp. 219-223 (1981), published in USA.
Rawson et al., Summation and Future Challenges, In: Inhibition of Tumor Induction and Development, Zedeck and Lipkin, editors, Plenum Press, New York, publishers, Chapter 9, pp. 219 223 (1981), published in USA. *
Schneeman et al., "Similar Effects of Zinc Deficiency and Restricted Feeding on Plasma Lipids and Lipoproteins in Rats," J. Nutr., 116:1889-1895 (1986), published in USA.
Schneeman et al., Similar Effects of Zinc Deficiency and Restricted Feeding on Plasma Lipids and Lipoproteins in Rats, J. Nutr., 116:1889 1895 (1986), published in USA. *
Takada et al., "Effect of β-Glucuronidase Inhibitor on Azoxymethane-Induced Colonic Carcinogenesis in Rats," Cancer Research, 42:331-334 (1982), published in USA.
Takada et al., Effect of Glucuronidase Inhibitor on Azoxymethane Induced Colonic Carcinogenesis in Rats, Cancer Research, 42:331 334 (1982), published in USA. *
The Merck Manual of Diagnosis and Therapy, Fourteenth Edition, Robert Berkow, M.D., Editor in Chief, Merck Sharp & Dohme Research Laboratories, Publishers, Chapter 82, Anomalies in Lipid Metabolism, pp. 970 977(1982), published in USA. *
The Merck Manual of Diagnosis and Therapy, Fourteenth Edition, Robert Berkow, M.D., Editor-in-Chief, Merck Sharp & Dohme Research Laboratories, Publishers, Chapter 82, "Anomalies in Lipid Metabolism," pp. 970-977(1982), published in USA.
The United States Pharmacopeia, the National Formulary, Twenty First Revision (Jan. 1, 1985), p. 48, Calcium Gluconate, published in USA. *
The United States Pharmacopeia, the National Formulary, Twenty-First Revision (Jan. 1, 1985), p. 48, Calcium Gluconate, published in USA.
Walaszek et al., "Antiproliferative Effect of Dietary Glucarate on the Sprague-Dawley Rat Mammary Gland," Cancer Letters, 49:51-57, (1990), published in Ireland.
Walaszek et al., "Antiproliferative Effects of Calcium D-Glucarate (CG) and D-Glucaro-1,4-Lactone (GL) on the Rat Mammary Gland, Colon and Mouse Skin," AACR Abstract Form (1990) printed in USA.
Walaszek et al., "Effect of Calcium D-Glucarate on Development of the Rat Mammary Gland and Its Sensitivity to Chemical Carcinogenesis," and D-Glucarate Control of Intestinal Bacterial Microflora and Relationship to Cancer Prevention, Proceedings of the American Association for Cancer Research, 33:164 (1992), Abstract Nos. 981 and 982, published in USA.
Walaszek et al., "Inhibition of 7,12-Dimethylbenzanthracene-Induced Rat Mammary Tumorigenesis by 2,5-DI-O-Acetyl-D-Glucaro-1,4:6,3-/Dilactone (Dagdl), an in Vivo β-Glucuronidase Inhibitor," Proceedings of the Seventh-Fifth Annual Meeting of the American Association for Cancer Research, May 9-12, (1984), 25:128, Abstract No. 507, published in Canada.
Walaszek et al., "Inhibition of 7,12-Dimethylbenzanthracene-Induced Rat Mammary Tumorigenesis by 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone, an in vivo β-glucuronidase Inhibitor," carcinogenesis, 5(6):767-772 (1984), published in United Kingdom.
Walaszek et al., Antiproliferative Effect of Dietary Glucarate on the Sprague Dawley Rat Mammary Gland, Cancer Letters, 49:51 57, (1990), published in Ireland. *
Walaszek et al., Antiproliferative Effects of Calcium D Glucarate (CG) and D Glucaro 1,4 Lactone (GL) on the Rat Mammary Gland, Colon and Mouse Skin, AACR Abstract Form (1990) printed in USA. *
Walaszek et al., Effect of Calcium D Glucarate on Development of the Rat Mammary Gland and Its Sensitivity to Chemical Carcinogenesis, and D Glucarate Control of Intestinal Bacterial Microflora and Relationship to Cancer Prevention, Proceedings of the American Association for Cancer Research, 33:164 (1992), Abstract Nos. 981 and 982, published in USA. *
Walaszek et al., Inhibition of 7,12 Dimethylbenzanthracene Induced Rat Mammary Tumorigenesis by 2,5 DI O Acetyl D Glucaro 1,4:6,3 /Dilactone (Dagdl), an in Vivo Glucuronidase Inhibitor, Proceedings of the Seventh Fifth Annual Meeting of the American Association for Cancer Research, May 9 12, (1984), 25:128, Abstract No. 507, published in Canada. *
Walaszek et al., Inhibition of 7,12 Dimethylbenzanthracene Induced Rat Mammary Tumorigenesis by 2,5 di O acetyl D glucaro 1,4:6,3 dilactone, an in vivo glucuronidase Inhibitor, carcinogenesis, 5(6):767 772 (1984), published in United Kingdom. *
Willett et al., "Relation of Serum Vitamins A and E and Carotenoids to the Risk of Cancer," the New England Journal of Medicine, 310(7):430-434 (1984), published in USA.
Willett et al., Relation of Serum Vitamins A and E and Carotenoids to the Risk of Cancer, the New England Journal of Medicine, 310(7):430 434 (1984), published in USA. *

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US7371415B1 (en) 1998-04-03 2008-05-13 The Daily Wellness Company Method and composition for improving sexual fitness
US20030203053A1 (en) * 1998-04-03 2003-10-30 Wuh Hank C.K. Method and composition for improving sexual fitness
US6368640B1 (en) 1998-04-03 2002-04-09 The Daily Wellness Company Method and composition for improving sexual fitness
US6103733A (en) * 1998-09-09 2000-08-15 Bachmann; Kenneth A. Method for increasing HDL cholesterol levels using heteroaromatic phenylmethanes
US20060159719A1 (en) * 1999-06-05 2006-07-20 The Board Of Trustees Of The Leland Stanford Junior University Method and composition for inhibiting cardiovascular cell proliferation
US20040074504A1 (en) * 1999-06-05 2004-04-22 Cooke John P. Method and composition for inhibiting cardiovascular cell proliferation
US20060167402A1 (en) * 1999-06-05 2006-07-27 The Board Of Trustees Of The Leland Stanford Junior University Method and composition for inhibiting cardiovascular cell proliferation
US20030026851A1 (en) * 2000-12-22 2003-02-06 Trant Aileen Sontag Method and composition for improving fertility health in female and male animals and humans
US6989164B2 (en) 2000-12-22 2006-01-24 The Daily Wellness Company Method and composition for improving male fertility health
US7045151B2 (en) 2000-12-22 2006-05-16 The Daily Wellness Company Method and composition for improving fertility health in female and male animals and humans
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US6596762B2 (en) 2001-05-17 2003-07-22 The Regents Of The University Of Colorado Antioxidant compositions and use for treatment of hepatic steatosis and steatohepatitis
US20070185203A1 (en) * 2004-03-01 2007-08-09 Rothbard Jonathan B Compositions and Methods for Treating Diseases
US7557087B2 (en) 2004-03-01 2009-07-07 Lumen Therapeutics, Llc Compositions and methods for treating diseases
US20050192210A1 (en) * 2004-03-01 2005-09-01 Rothbard Jonathan B. Compositions and methods for treating diseases
US8961813B2 (en) 2006-08-07 2015-02-24 The University Of Montana Hydroxycarboxylic acids and salts
US9162959B2 (en) 2006-08-07 2015-10-20 The University Of Montana Method of oxidation using nitric acid
US20090250653A1 (en) * 2006-08-07 2009-10-08 Kiely Donald E Hydroxycarboxylic Acids and Salts
US20100247505A1 (en) * 2007-10-25 2010-09-30 Nutri Co., Ltd. Composition for Reducing the Level of Glucose, Malondialdehyde-Modified LDL, Homocysteine and/or C-Reactive Protein in Blood
US10383893B2 (en) * 2007-10-25 2019-08-20 Nutri Co., Ltd. Composition for reducing the level of glucose, malondialdehyde-modified LDL, homocysteine and/or C-reactive protein in blood
US8623943B2 (en) 2007-11-15 2014-01-07 The University Of Montana Hydroxypolyamide gel forming agents
US20090131259A1 (en) * 2007-11-15 2009-05-21 Kiely Donald E Hydroxypolyamide Gel Forming Agents
US9315624B2 (en) 2007-11-15 2016-04-19 The University Of Montana Hydroxypolyamide gel forming agents
US9505882B2 (en) 2007-11-15 2016-11-29 The University Of Montana Hydroxypolyamide gel forming agents
US9404188B2 (en) 2010-11-11 2016-08-02 Rivertop Renewables Corrosion inhibiting composition
US9347024B2 (en) 2011-04-21 2016-05-24 Rivertop Renewables, Inc. Calcium sequestering composition
US9096787B2 (en) 2012-11-28 2015-08-04 Rivertop Renewables Corrosion inhibiting, freezing point lowering compositions
US9187398B2 (en) 2013-03-13 2015-11-17 Rivertop Renewables, Inc. Nitric acid oxidation processes
US9346736B2 (en) 2013-03-13 2016-05-24 Rivertop Renewables, Inc. Oxidation process
US9670124B2 (en) 2013-03-13 2017-06-06 Rivertop Renewables, Inc. Nitric acid oxidation process
US9758462B2 (en) 2013-03-13 2017-09-12 Rivertop Renewables, Inc. Nitric acid oxidation processes

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EP0528950A1 (en) 1993-03-03
EP0528950B1 (en) 1996-09-11
EP0528950A4 (en) 1993-03-24
JPH06504259A (en) 1994-05-19
ATE142489T1 (en) 1996-09-15
EP0730862A1 (en) 1996-09-11
DE69122099D1 (en) 1996-10-17
DE69122099T2 (en) 1997-04-17
CA2080818A1 (en) 1991-11-17

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